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Exome sequencing links CEP120 mutation to maternally derived aneuploid conception risk

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Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Genre (authority = RULIB-FS)
Article, Refereed
Genre (authority = NISO JAV)
Accepted Manuscript (AM)
Genre (authority = ExL-Esploro)
Accepted manuscript
Abstract (type = abstract)
Study question: What are the genetic factors that increase the risk of aneuploid egg production?

Summary answer: A non-synonymous variant rs2303720 within centrosomal protein 120 (CEP120) disrupts female meiosis in vitro in mouse.

What is known already: The production of aneuploid eggs, with an advanced maternal age as an established contributing factor, is the major cause of IVF failure, early miscarriage and developmental anomalies. The identity of maternal genetic variants contributing to egg aneuploidy irrespective of age is missing.

Study design, size, duration: Patients undergoing fertility treatment (n = 166) were deidentified and selected for whole-exome sequencing.

Participants/materials, setting, methods: Patients self-identified their ethnic groups and their ages ranged from 22 to 49 years old. The study was performed using genomes from White, non-Hispanic patients divided into controls (97) and cases (69) according to the number of aneuploid blastocysts derived during each IVF procedure. Following a gene prioritization strategy, a mouse oocyte system was used to validate the functional significance of the discovered associated genetic variants.

Main results and the role of chance: Patients producing a high proportion of aneuploid blastocysts (considered aneuploid if they missed any of the 40 chromatids or had extra copies) were found to carry a higher mutational burden in genes functioning in cytoskeleton and microtubule pathways. Validation of the functional significance of a non-synonymous variant rs2303720 within Cep120 on mouse oocyte meiotic maturation revealed that ectopic expression of CEP120:p.Arg947His caused decreased spindle microtubule nucleation efficiency and increased incidence of aneuploidy.

Limitations, reasons for caution: Functional validation was performed using the mouse oocyte system. Because spindle building pathways differ between mouse and human oocytes, the defects we observed upon ectopic expression of the Cep120 variant may alter mouse oocyte meiosis differently than human oocyte meiosis. Further studies using knock-in 'humanized' mouse models and in human oocytes will be needed to translate our findings to human system. Possible functional differences of the variant between ethnic groups also need to be investigated.

Wider implications of the findings: Variants in centrosomal genes appear to be important contributors to the risk of maternal aneuploidy. Functional validation of these variants will eventually allow prescreening to select patients that have better chances to benefit from preimplantation genetic testing.
TypeOfResource
Text
TitleInfo
Title
Exome sequencing links CEP120 mutation to maternally derived aneuploid conception risk
PhysicalDescription
Extent
1 online resource (51 pages) : illustrated
Subject (authority = local)
Topic
Fertility
Subject (authority = local)
Topic
IVF
Subject (authority = local)
Topic
Aneuploidy
Subject (authority = local)
Topic
Exome sequencing
Subject (authority = local)
Topic
Centrosomal protein 120
Subject (authority = local)
Topic
Oocyte maturation
Subject (authority = local)
Topic
Chromosome segregation
Subject (authority = local)
Topic
Microtubule organizing centers
Subject (authority = local)
Topic
Spindle
Name (type = personal)
NamePart (type = family)
Tyc
NamePart (type = given)
Katarzyna M.
Role
RoleTerm (authority = marcrt); (type = text)
author
Affiliation
Genetics, Rutgers University
Name (type = personal)
NamePart (type = family)
El Yakoubi
NamePart (type = given)
Warif
Role
RoleTerm (authority = marcrt); (type = text)
author
Affiliation
Genetics, Rutgers University
Name (type = personal)
NamePart (type = family)
Bag
NamePart (type = given)
Aishee
Role
RoleTerm (authority = marcrt); (type = text)
author
Affiliation
Genetics, Rutgers University
Name (type = personal)
NamePart (type = family)
Landis
NamePart (type = given)
Jessica
Role
RoleTerm (authority = marcrt); (type = text)
author
Affiliation
Foundation for Embryonic Competence
Name (type = personal)
NamePart (type = family)
Zhan
NamePart (type = given)
Yiping
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RoleTerm (authority = marcrt); (type = text)
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Affiliation
Foundation for Embryonic Competence
Name (type = personal)
NamePart (type = family)
Treff
NamePart (type = given)
Nathan R.
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author
Affiliation
Reproductive Medicine Associates of New Jersey
Name (type = personal)
NamePart (type = family)
Scott
NamePart (type = given)
Richard T.
NamePart (type = termsOfAddress)
Jr.
Role
RoleTerm (authority = marcrt); (type = text)
author
Affiliation
Reproductive Medicine Associates of New Jersey
Name (type = personal)
NamePart (type = family)
Tao
NamePart (type = given)
Xin
Role
RoleTerm (authority = marcrt); (type = text)
author
Affiliation
Foundation for Embryonic Competence
Name (type = personal)
NamePart (type = family)
Schindler
NamePart (type = given)
Karen
Role
RoleTerm (authority = marcrt); (type = text)
author
Affiliation
Genetics, Rutgers University
Name (authority = orcid); (authorityURI = http://id.loc.gov/vocabulary/identifiers/orcid.html); (type = personal); (valueURI = http://orcid.org/0000-0001-6469-8733)
NamePart (type = family)
Xing
NamePart (type = given)
Jinchuan
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RoleTerm (authority = marcrt); (type = text)
author
Affiliation
Genetics, Rutgers University
OriginInfo
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2020
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Citation
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Journal
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Name
Human Reproduction
Identifier (type = volume and issue)
35(9)
Reference (type = url)
https://doi.org/10.1093/humrep/deaa148
Detail
2134-2148
DateTime (encoding = w3cdtf)
2020
RelatedItem (type = has document)
TitleInfo
Title
Whole exome sequencing identifies centrosomal component gene mutations that increase human aneuploid conception risk, supplemental data
Identifier (type = doi)
doi:10.7282/t3-xq8d-ap68
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TitleInfo
Title
Xing, Jinchuan
Identifier (type = local)
rucore30185800001
Name (authority = RutgersOrg-Department); (type = corporate)
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Genetics
Name (authority = RutgersOrg-School); (type = corporate)
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School of Arts and Sciences (SAS) (New Brunswick)
Note (type = peerReview)
Peer reviewed
Location
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Identifier (type = doi)
doi:10.7282/t3-gyq3-c907
Note
Supplemental data: https://doi.org/doi:10.7282/t3-xq8d-ap68
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2020-08-09
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2021-08-09
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